Methods for prevention and treatment of attention deficit disorder

ABSTRACT

Patients susceptible to or suffering from attention deficit disorder are treated by administering an effective amount of an aryl subsistituted aliphatic compound, an aryl substituted olefinic amine compound or an aryl substituted acetylenic compound. Exemplary compounds are (E)-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-4- 3-(5-methoxypyridin)yl!-3-butene-1-amine, (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-N-methyl-4- 3-(5-methoxypyrindin)yl!-3-butene-1-amine, (Z)-metanicotine, (E)-metanicotine, N-methyl-(3-pyridinyl)-butane-1-amine, N-methyl-4-(3-pyridinyl)-3-butyne-1-amine and (E)-N-methyl-4- 3-(6-methylpyrindin)yl!-3-butene-1-amine.

This application is a continuation of Ser. No. 08/364,978, filed Jan. 6,1995, now U.S. Pat. No. 5,731,314.

BACKGROUND OF THE INVENTION

The present invention relates to compounds having pharmaceuticalproperties, and in particular, to compounds useful for preventing andtreating central nervous system (CNS) disorders. The present inventionrelates to a method for treating patients suffering from or susceptibleto such disorders, and in particular, to a method for treating patientssuffering from those disorders which are associated withneurotransmitter system dysfunction. The present invention also relatesto compositions of matter useful as pharmaceutical compositions in theprevention and treatment of CNS disorders which have been attributed toneurotransmitter system dysfunction.

CNS disorders are a type of neurological disorder. CNS disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses;and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a cholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency and/or a serotonergic deficiency. CNS disorders of relativelycommon occurrence include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),Parkinsonism including Parkinson's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety,dyslexia, schizophrenia and Tourette's syndrome.

Senile dementia of the Alzheimer's type (SDAT) is a debilitatingneurodegenerative disease, mainly afflicting the elderly; characterizedby a progressive intellectual and personality decline, as well as a lossof memory, perception, reasoning, orientation and judgment. One featureof the disease is an observed decline in the function of cholinergicsystems, and specifically, a severe depletion of cholinergic neurons(i.e., neurons that release acetylcholine, which is believed to be aneurotransmitter involved in learning and memory mechanisms). See,Jones, et al., Intern. J. Neurosci., Vol. 50, p. 147 (1990); Perry, Br.Med. Bull., Vol. 42, p. 63 (1986) and Sitaram. et al., Science, Vol.201,p. 274 (1978). It has been observed that nicotinic acetylcholinereceptors, which bind nicotine and other nicotinic agonists with highaffinity, are depleted during the progression of SDAT. See, Giacobini,J. Neurosci. Res., Vol. 27, p. 548 (1990); and Baron, Neurology, Vol.36, p. 1490 (1986). As such, it would seem desirable to providetherapeutic compounds which either directly activate nicotinic receptorsin place of acetylcholine or act to minimize the loss of those nicotinicreceptors.

Certain attempts have been made to treat SDAT. For example, nicotine hasbeen suggested to possess an ability to activate nicotinic cholinergicreceptors upon acute administration, and to elicit an increase in thenumber of such receptors upon chronic administration to animals. See,Rowell, Adv. Behav. Biol., Vol. 31, p. 191 (1987); and Marks, J.Pharmacol. Exp. Ther., Vol. 226, p. 817 (1983). It also has beenproposed that nicotine can act directly to elicit the release ofacetylcholine in brain tissue, to improve cognitive functions, and toenhance attention. See, Rowell, et al., J. Neurochem., Vol. 43, p. 1593(1984); Sherwood, Human Psychopharm., Vol. 8, pp. 155-184 (1993);Hodges, et al., Bio. of Nic., Edit. by Lippiello, et al., p. 157 (1991);Sahakian, et al., Br. J. Psych., Vol. 154, p. 797 (1989); and U.S. Pat.Nos. 4,965,074 to Leeson and 5,242,935 to Lippiello et al. Other methodsfor treating SDAT have been proposed, including U.S. Pat. Nos. 5,212,188to Caldwell et al. and 5,227,391 to Caldwell et al. and European PatentApplication No. 588,917. Another proposed treatment for SDAT is Cognex,which is a capsule containing tacrine hydrochloride, available fromParke-Davis Division of Warner-Lambert Company, which reportedlypreserves existing acetylchloine levels in patients treated therewith.

Parkinson's disease (PD) is a debilitating neurodegenerative disease,presently of unknown etiology, characterized by tremors and muscularrigidity. A feature of the disease appears to involve the degenerationof dopaminergic neurons (i.e., which secrete dopamine). One symptom ofthe disease has been observed to be a concomitant loss of nicotinicreceptors which are associated with such dopaminergic neurons, and whichare believed to modulate the process of dopamine secretion. See, Rinne,et al., Brain Res., Vol. 54, pp. 167-170 (1991) and Clark, et al., Br.J. Pharm., Vol. 85, pp. 827-835 (1985). It also has been proposed thatnicotine can ameliorate the symptoms of PD. See, Smith et al., Rev.Neurosci., Vol. 3(1), pp. 25-43 (1982).

Certain attempts have been made to treat PD. One proposed treatment forPD is Sinemet CR, which is a sustained-release tablet containing amixture of carbidopa and levodopa, available from The DuPont MerckPharmaceutical Co. Another proposed treatment for PD is Eldepryl, whichis a tablet containing selefiline hydrochloride, available from SomersetPharmaceuticals, Inc. Another proposed treatment for PD is Parlodel,which is a tablet containing bromocriptine mesylate, available fromSandoz Pharmaceuticals Corporation. Another method for treating PD and avariety of other neurodegenerative diseases has been proposed in U.S.Pat. No. 5,210,076 to Berliner et al.

Tourette's syndrome (TS) is an autosomal dominant neuropsychiatricdisorder characterized by a range of neurological and behavioralsymptoms. Typical symptoms include (i) the onset of the disorder beforethe age of 21 years, (ii) multiple motor and phonic tics although notnecessarily concurently, (iii) varience in the clinical phenomenology ofthe tics, and (iv) occurrence of quasi daily tics throughout a period oftime exceeding a year. Motor tics generally include eye blinking, headjerking, shoulder shrugging and facial grimacing; while phonic or vocaltics include throat clearing, sniffling, yelping, tongue clicking anduttering words out of context. The pathophysiology of TS presently isunknown, however it is believed that neurotransmission dysfunction isimplicated with the disorder. See, Calderon-Gonzalez et al., Intern.Pediat., Vol. 8(2), pp. 176-188 (1993) and Oxford Textbook of Medicine,Eds. Weatherall et al., Chapter 21.218 (1987).

It has been proposed that nicotine pharmacology is beneficial insuppressing the symptoms associated with TS. See, Devor et al., TheLancet, Vol. 8670, p. 1046 (1989); Jarvik, British J. of Addiction, Vol.86, pp. 571-575 (1991); McConville et al., Am. J. Psychiatry, Vol. 148(6), pp. 793-794 (1991); Newhouse et al., Brit. J. Addic., Vol. 86, pp.521-526 (1991); McConville et al., Biol. Psychiatry, Vol. 31, pp.832-840 (1992); and Sanberg et al., Proceedings from Intl. Symp. Nic.,S39 (1994). It also has been proposed to treat TS using Haldol, which ishaloperidol available from McNeil Pharmaceutical; Catapres, which isclonidine available from Boehringer Ingelheim Pharmaceuticals, Inc.,Orap, which is pimozide available from Gate Pharmaceuticals; Prolixin,which is fluphenazine available from Apothecon Division of Bristol-MyersSquibb Co.; and Klonopin, which is clonazepam available fromHoffmann-LaRoche Inc.

Attention deficit disorder (ADD) is a disorder which affects mainlychildren, although ADD can affect adolescents and adults. See, Vinson,Arch. Fam. Med., Vol. 3(5), pp. 445-451 (1994); Hechtman, J. PsychiatryNeurosci., Vol. 19 (3), pp. 193-201 (1994); Faraone et al., Biol.Psychiatry, Vol. 35(6), pp. 398-402 (1994) and Malone et al., J. ChildNeurol., Vol. 9(2), pp. 181-189 (1994). Subjects suffering from thedisorder typically have difficulty concentrating, listening, learningand completing tasks; and are restless, fidgety, impulsive and easilydistracted. Attention deficit disorder with hyperactivity (ADHD)includes the symptoms of ADD as well as a high level of activity (e.g.,restlessness and movement). Attempts to treat ADD have involvedadministration of Dexedrine, which is a sustained release capsulecontaining detroamphetamine sulfate, available from SmithKline BeechamPharmaceuticals; Ritalin, which is a tablet containing methylphenidatehydrochloride, available from Ciba Pharmaceutical Company; and Cylert,which is a tablet containing premoline, available from AbbottLaboratories. In addition, it has been reported that administration ofnicotine to an individual improves that individual's selective andsustained attention. See, Warburton et al., Cholinergic control ofcognitive resources, Neuropsychobiology, Eds. Mendlewicz, et al., pp43-46 (1993).

Schizophrenia is characterized by psychotic symptoms includingdelusions, catatonic behavior and prominent hallucinations, andultimately results in a profound decline in the psychosocial affect ofthe subject suffering therefrom. Traditionally, schizophrenia has beentreated with Klonopin, which is available as a tablet containingclonezepam, available from Hoffmann-LaRoche Inc.; Thorazine, which isavailable as a tablet containing chlorpromazine, available fromSmithKline Beecham Pharmaceuticals; and Clozaril, which is a tabletcontaining clozapine, available from Sandoz Pharmaceuticals. Suchneuroleptics are believed to be effective as a result of interactionthereof with the dopaminergic pathways of the CNS. In addition, adopaminergic dysfunction possessed by individuals suffering fromschizophrenia has been proposed. See, Lieberman et al., Schizophr.Bull., Vol. 19, pp. 371-429 (1993) and Glassman, Amer. J. Psychiatry,Vol. 150, pp. 546-553 (1993). Nicotine has been proposed as beingeffective in effecting neurotransmitter disfunction associated withschizophremia. See, Merriam et al., Psychiatr. Annals, Vol. 23, pp.171-178 (1993) and Adler et al., Biol. Psychiatry, Vol. 32, pp. 607-616(1992).

Nicotine has been proposed to have a number of pharmacological effects.Certain of those effects may be related to effects upon neurotransmitterrelease. See, for example, Sjak-shie et al., Brain Res., Vol. 624, pp.295-298 (1993), where neuroprotective effects of nicotine are proposed.Release of acetylcholine and dopamine by neurons upon administration ofnicotine has been reported by Rowell et al., J. Neurochem., Vol. 43, pp.1593-1598 (1984); Rapier et al., J. Neurochem., Vol. 50, pp. 1123-1130(1988); Sandor et al., Brain Res., Vol. 567, pp. 313-316 (1991) andVizi, Br. J. Pharmacol., Vol. 47, pp. 765-777 (1973). Release ofnorepinephrine by neurons upon administration of nicotine has beenreported by Hall et al., Biochem. Pharmacol., Vol. 21, pp. 1829-1838(1972). Release of serotonin by neurons upon administration of nicotinehas been reported by Hery et al., Arch. Int. Pharmacodyn. Ther., Vol.296, pp. 91-97 (1977). Release of glutamate by neurons uponadministration of nicotine has been reported by Toth et al., NeurochemRes., Vol. 17, pp. 265-271 (1992). Therefore, it would be desirable toprovide a pharmaceutical composition containing an active ingredienthaving nicotinic pharmacology, which pharmaceutical composition iscapable of illicting neurotransmitter release within a subject in orderto prevent or treat a neurological disorder. In addition, nicotinereportedly potentiates the pharmacological behavior of certainpharmaceutical compositions used for the treatment of certain CNSdisorders. See, Sanberg et al., Pharmacol. Biochem. & Behavior, Vol. 46,pp. 303-307 (1993); Harsing et al., J. Neurochem., Vol. 59, pp. 48-54(1993) and Hughes, Proceedings from Intl. Symp. Nic., S40 (1994).Furthermore, various other beneficial pharmacological effects ofnicotine have been proposed. See, Decina et al., Biol. Psychiatry, Vol.28, pp. 502-508 (1990); Wagner et al., Pharmacopsychiatry, Vol. 21, pp.301-303 (1988); Pomerleau et al., Addictive Behaviors, Vol. 9, p. 265(1984); Onaivi et al., Life Sci., Vol. 54(3), pp. 193-202 (1994) andHamon, Trends in Pharmacol. Res., Vol. 15, pp. 36-39.

It would be desirable to provide a useful method for the prevention andtreatment of a CNS disorder by administering a nicotinic compound to apatient suseptible to or suffering from such a disorder. It would behighly beneficial to provide individuals suffering from certain CNSdisorders with interruption of the symptoms of those diseases by theadministration of a pharmaceutical composition which has nicotinicpharmacology and which has a beneficial effect upon the functioning ofthe CNS, but which does not provide any significant associated sideeffects (e.g., increased heart rate and blood pressure) attendant withinteraction of that compound with cardiovascular sites. It would behighly desirable to provide a pharmaceutical composition incorporating acompound which interacts with nicotinic receptors which have thepotential to affect the functioning of the CNS, but which does notsignificantly affect those receptors which have the potential to induceundesirable side effects (e.g., appreciable pressor cardiovasculareffects and appreciable activity at skeletal muscle sites).

SUMMARY OF THE INVENTION

The present invention relates to aryl substituted aliphatic aminecompounds, aryl substituted olefinic amine compounds and arylsubstituted acetylenic amine compounds.

The present invention relates to a method for providing prevention ortreatment of a central nervous system (CNS) disorder. The methodinvolves administering to a subject an effective amount of a compound ofthe present invention.

The present invention, in another aspect, relates to a pharmaceuticalcomposition comprising an effective amount of a compound of the presentinvention. Such a pharmaceutical composition incorporates a compoundwhich has the capability of interacting with relevant nicotinic receptorsites of a subject, and hence has the capability of acting as atherapeutic in the prevention or treatment of a CNS disorder.

The pharmaceutical compositions of the present invention are useful forthe prevention and treatment of CNS disorders. The pharmaceuticalcompositions provide therapeutic benefit to individuals suffering fromcertain CNS disorders and exhibiting clinical manifestations of suchdisorders in that the compounds within those compositions have thepotential to (i) exhibit nicotinic pharmacology and affect nicotinicreceptors sites in the CNS (e.g., act as a pharmacological agonist toactivate nicotinic receptors), and (ii) elicit neurotransmittersecretion, and hence prevent and suppress the symptoms associated withthose diseases. In addition, the compounds are expected to have thepotential to (i) increase the number of nicotinic cholinergic receptorsof the brain of the patient, (ii) exhibit neuroprotective effects and(iii) not provide appreciable adverse side effects (e.g., significantincreases in blood pressure and heart rate, and significant effects uponskeletal muscle). The pharmaceutical compositions of the presentinvention are believed to be safe and effective with regards toprevention and treatment of CNS disorders.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention, in one aspect, relates to certain compoundshaving the formula: ##STR1## where X is nitrogen or carbon bonded to asubstituent species characterized as having a sigma m value greater than0, often greater than 0.1, generally greater than 0.2 and even greaterthan 0.3; less than 0 and generally less than -0.1; or 0; as determinedin accordance with Hansch et al., Chem. Rev., Vol. 91, pp. 165-195(1991); n is an integer which can range from 1 to 5, preferably from 1to 3, and most preferably is 2 or 3; Z' and Z" individually representhydrogen or lower alkyl (e.g., alkyl containing one to five carbonatoms, such as methyl, ethyl or isopropyl), and preferably at least oneof Z' and Z" is hydrogen; A, A' and A" individually represent hydrogen,alkyl (e.g., lower straight chain or branched alkyl, including C₁ -C₇,but preferably methyl or ethyl) or halo (e.g., F, Cl, Br or I); thedashed line in the structure represents a C--C single bond, a C--Cdouble bond or a C--C triple bond; the wavy line in the structurerepresents a cis (Z) or trans (E) form of the compound when the dashedline is a C--C double bond; and X' represents CH₂ when the dashed lineis a C--C single bond, CH when the dashed line is a C--C double bond,and C when the dashed line is a C--C triple bond. X includes N, C--H,C--F, C--Cl, C--Br, C--I, C--NR'R", C--CF₃, C--OH, C--CN, C--SH,C--SCH₃, C--N₃, C--SO₂ CH₃, C--OR', C--C(═O)N R'R", C--NR'C(═O)R',C--C(═O)OR', C--OC(═O)R', C--OC(═O)NR'R" and C--NR'C(═O)OR' where R' andR" are individually hydrogen or lower alkyl (e.g., alkyl containing oneto five carbon atoms, preferably methyl or ethyl). When X represents acarbon atom bonded to a substituent species, that substitutent speciesoften has a sigma m value which is between about -0.3 and about 0.75,and frequently between about -0.25 and about 0.6. In certaincircumstances when X represents a carbon atom bonded to a substituentspecies, the dashed line is a C--C double bond and the compound has thetrans (E) form, the substituent species is characterized as having asigma m value not equal to 0. Particularly when the dashed line is aC--C double bond, the compound has the trans (E) form, A, A', A" and Z'all are hydrogen, n is 2, and Z" is methyl, the substituent species ischaracterized as having a sigma m value not equal to 0. In addition, itis highly preferred that A is hydrogen, it is preferred that A' ishydrogen, and normally A" is hydrogen. Generally, both A and A' arehydrogen; sometimes A and A' are hydrogen, and A" is methyl or ethyl;and often A, A' and A" are all hydrogen. One representative compound isN-methyl-4-(3-pyridinyl)-butane-1-amine for which for which the dashedline is a C--C single bond, X' is CH₂, X is C--H, n is 2, and A, A', A"and Z' each are hydrogen, and Z" is methyl. Another representativecompound is N-methyl-4-(3-pyridinyl)-3-butyne-1-amine for which forwhich the dashed line is a C--C triple bond, X' is C, X is C--H, n is 2,and A, A', A" and Z' each are hydrogen, and Z" is methyl. Otherrepresentative compounds are (Z)-metanicotine and (E)-metanicotine, forwhich the dashed line is a C--C double bond, X' is CH, n is 2, and A,A', A" and Z' each are hydrogen, and Z" is methyl. Of particularinterest are compounds having the formula: ##STR2## where n, X, A, A',A", Z' and Z" are as defined hereinbefore, and those compounds can havethe cis (Z) or trans (E) form. For such compounds of pariticularinterest, X most preferably is nitrogen or carbon bonded to asubstituent species characterized as having a sigma m value greater than0, often greater than 0.1, generally greater than 0.2 and even greaterthan 0.3; less than 0 and gonerally less than -0.1; or 0. Onerepresentative compound is (E)-4-(5-pyrimidinyl)-3-butene-1-amine forwhich X is N, n is 2, and A, A', A", Z' and Z" each are hydrogen.Another representative compound is (E)-4-3-(5-methoxypyridin)yl!-3-butene-1-amine for which X is C--OCH₃, n is 2,and A, A', A", Z' and Z" each are hydrogen. Another representativecompound is (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine for which Xis N, n is 2, A, A', A", and Z' are each hydrogen, and Z" is methyl.Another representative compound is (E)-N-methyl-4-3-(5-methoxypyridin)yl!-3-butene-1-amine for which X is C--OCH₃, n is 2,and A, A', A", and Z' are each hydrogen, and Z" is methyl. Anotherrepresentative compound is (E)-4-3-(5-ethoxypyridin)yl!-3-butene-1-amine for which X is C--OCH₂ CH₃, n is2, and A, A', A", Z' and Z" each are hydrogen. Another representativecompound is (E)-N-methyl-4- 3-(5-ethoxypyridin)yl!-3-butene-1-amine forwhich X is C--OCH₂ CH₃, n is 2, A, A', A" and Z' each are hydrogen, andZ" is methyl. Another representative compound is (E)-4-3-(5-aminopyridin)yl!-3-butene-1-amine for which X is C--NH₂, n is 2,and A, A', A", Z' and Z" each are hydrogen. Another representativecompound is (E)-N-methyl-4- 3-(5-aminopyridin)yl!-3-butene-1-amine forwhich X is C--NH₂, n is 2, A, A', A" and Z' each are hydrogen, and Z" ismethyl. Another representative compound is (E)-4-3-(5-bromopyridin)yl!-3-butene-1-amine for which X is C--Br, n is 2, andA, A', A", Z' and Z" each are hydrogen. Another representative compoundis (E)-N-methyl-4- 3-(5-bromopyridin)yl!-3-butene-1-amine for which X isC--Br, n is 2, A, A', A" and Z' each are hydrogen, and Z" is methyl.Another representative compound is (E)-4-3-(5-methoxy-6-methylpyridin)yl!-3-butene-1-amine for which X isC--OCH₃, n is 2, A" is methyl, and A, A', Z' and Z" each are hydrogen.Another representative compound is (E)-N-methyl-4-3-(5-methoxy-6-methylpyridin)yl!-3-butene-1-amine for which X isC--OCH₃, n is 2, A" and Z" each are methyl, and A, A'and Z' each arehydrogen. Another representative compound is (E)-N-methyl-4-3-(6-methylpyridin)yl!-3-butene-1-amine for which X is C--H, n is 2, A"and Z" each are methyl, and A, A' and Z' each are hydrogen. Anotherrepresentative compound is (E)-4-3-(6-methylpyridin)yl!-3-butene-1-amine for which X is C--H, n is 2, A"is methyl, and A, A', Z' and Z" each are hydrogen. Anotherrepresentative compound is (E)-N-methyl-5-3-pyridinyl!-4-pentene-1-amine for which X is C--H, n is 3, Z" ismethyl, and A, A', A" and Z' are each hydrogen. Another representativecompound is (E)-N-(2-propyl)-4- 3-pyridynyl!-3-butene-1-amine for whichX is C--H, n is 2, Z" is isopropyl, and A, A', A" and Z' are eachhydrogen.

The manner in which aryl substituted aliphatic amine compounds of thepresent invention are synthetically produced can vary. Preparation ofvarious aryl substituted aliphatic amine compounds can be carried outusing the types of techniques disclosed by Rondahl, Acta Pharm. Suec.,Vol. 13, pp. 229-234 (1976). Certain metanicotine-type compounds thatpossess a saturated side chain rather than an olefinic side chain can beprepared by hydrogenation of the corresponding metanicotine-typecompounds or the corresponding acetylenic precursors. For example,dihydrometanicotine can be prepared by hydrogenation of (E)-metanicotineas described by Kamimura et al., Agr. Biol. Chem., Vol. 27, No. 10, pp.684-688 (1963).

The manner in which aryl substituted acetylenic amine compounds of thepresent invention are synthetically produced can vary. For example, anaryl substituted acetylenic amine compound, suchN-methyl-4-(3-pyridinyl)-3-butyne-1-amine, can be prepared using anumber of synthetic steps: (i) conversion of 3-pyridinecarboxaldehyde toa 1,1-dihalo-2-(3-pyridinyl)-ethylene using a carbon tetrahalide andtriphenylphosphine, (ii) side chain elaboration of this intermediate byreaction with butyl lithium and ethylene oxide, affording4-(3-pyridinyl)-3-butyn-1-ol, (iii) conversion of this intermediate toits methanesulfonate ester, and (iv) mesylate displacement with methylamine, affording N-methyl-4-(3-pyridinyl)-3-butyne-1-amine.

The manner in which aryl substituted olefinic amine compounds of thepresent invention are s ynthetically produced can vary. (E)-metanicotinecan be prepared using the techniques set forth by Loffler et al., Chem.Ber., Vol. 42, pp. 3431-3438 (1909) and Laforge, J.A.C.S., Vol. 50, p.2477 (1928). Certain novel 6-substituted metanicotine-type compounds canbe prepared from the corresponding 6-substituted nicotine-type compoundsusing the general methods of Acheson et al., J. Chem. Soc., PerkinTrans. 1, Vol. 2, pp. 579-585 (1980). The requisite precursors for suchcompounds, 6-substituted nicotine-type compounds, can be synthesizedfrom 6-substituted nicotinic acid esters using the general methodsdisclosed by Rondahl, Acta Pharm. Suec., Vol. 14, pp 113-118 (1977).Preparation of certain 5-substituted metanicotine-type compounds can beaccomplished from the corresponding 5-substituted nicotine-typecompounds using the general method taught by Acheson et al., J. Chem.Soc., Perkin Trans. 1, Vol. 2, pp. 579-585 (1980). The 5-halonicotine-type compounds (e.g., fluoro and bromo nicotine-type compounds)and the 5-amino nicotine-type compounds can be prepared using thegeneral procedures disclosed by Rondahl, Act. Pharm. Suec., Vol. 14, pp.113-118 (1977). The 5-trifluoromethyl nicotine-type compounds can beprepared using the techniques and materials set forth in Ashimori etal., Chem. Pharm. Bull., Vol. 38(9), pp. 2446-2458 (1990) and Rondahl,Acta Pharm. Suec., Vol. 14, pp. 113-118 (1977). Furthermore, preparationof certain metanicotine-type compounds can be accomplished using apalladium catalyzed coupling reaction of an aromatic halide and aterminal olefin containing a protected amine substituent, removal of theprotective group to obtain a primary amine, and optional alkylation toprovide a secondary or tertiary amine. In particular, certainmetanicotine-type compounds can be prepared by subjecting a 3-halosubstituted, 5-substituted pyridine compound or a 5-halo substitutedpyrimidine compound to a palladium catalyzed coupling reaction using anolefin possessing a protected amine functionality (e.g., such an olefinprovided by the reaction of a phthalimide salt with 3-halo-1-propene,4-halo-1-butene, 5-halo-1-pentene or 6-halo-1-hexene). See, Frank etal., J. Org. Chem., Vol. 43(15), pp. 2947-2949 (1978) and Malek et al.,J. Org. Chem., Vol. 47, pp. 5395-5397 (1982). Alternatively, certainmetanicotine-type compounds can be prepared by coupling an N-protected,modified amino acid residue, such as4-(N-methyl-N-tert-butyloxycarbonyl)aminobutyric acid methyl ester, withan aryl lithium compound, as can be derived from a suitable aryl halideand butyl lithium. The resulting N-protected aryl ketone is thenchemically reduced to the corresponding alcohol, converted to the alkylhalide, and subsequently dehydrohalogenated to introduce the olefinfunctionality. Removal of the N-protecting group affords the desiredmetanicotine-type compound. There are a number of different methods forproviding (Z)-metanicotine-type compounds. In one method,(Z)-metanicotine-type compounds can be synthesized from nicotine-typecompounds as a mixture of E and Z isomers; and the (Z)-metanicotine-typecompounds can then be separated by chromatography using the types oftechniques disclosed by Sprouse et al., Abstracts of Papers, p. 32,Coresta/TCRC Joint Conference (1972). In another method,(Z)-metanicotine can be prepared by the controlled hydrogenation of thecorresponding acetylenic compound (e.g.,N-methyl4-(3-pyridinyl)-3-butyne-1-amine). For example, certain5-substituted (Z)-metanicotine-type compounds and certain 6-substituted(Z)-metanicotine-type compounds can be prepared from5-substituted-3-pyridinecarboxaldehydes and6-substituted-3-pyridinecarboxaldehydes, respectively.

A representative compound, (E)-N-methyl-4-3-(5-bromopyridin)yl!-3-butene-1-amine, can be synthesized using thefollowing representative procedure: 5-Bromonicotine (0.018 mole) in 10ml of methylene chloride dried over phosphorous pentaoxide has asolution of ethyl chloroformate (0.018 mole) in 10 mL of similarly driedmethylene chloride added dropwise over 10 to 15 minutes. The resultingmixture then is refluxed under nitrogen atmosphere for about 3 hours.Then, the methylene chloride is removed using a rotary evaporator, andthe remaining material is distilled under reduced pressure to yield aN-ethylcarbamate derivative of 5-bromometanicotine product as a thickliquid which has a boiling point of 182° C. at 0.04 mm Hg. This product(0.08 mole) is then refluxed for several hours in 15 ml of concentratedaqueous hydrochloric acid. The resulting reaction mixture was cooled andbasified to pH 8-9 using concentrated aqueous sodium hydroxide while themixture is maintained at a temperature of about 0° C. The resultingproduct is extracted four times with 20 ml quantities of chloroform, andthe combined collected fractions are dried over anhydrous sodiumsulfate. Then, the chloroform is removed using a rotary evaporator, andthe remaining material is distilled under reduced pressure to yield the(E)-N-methyl-4- 3-(5-bromopyridin)yl!-3-butene-1-amine product as acolorless liquid which has a boiling point of 115° C. at 0.04 mm Hg.That product can be converted to a fumarate salt, which has a meltingpoint of 148°-150° C.

A representative compound, (E)-N-methyl-5-3-pyridinyl!-4-pentene-1-amine, can be synthesized using the followingrepresentative procedure. A solution of N-methyl anabasine (0.011 mole)in 100 mL methylene chloride is added dropwise into a slight molarexcess of ethyl chloroformate in 100 mL methylene chloride undernitrogen atmosphere in a flask equipped with a condenser. Then, themixture is refluxed for about 3 hours. Then, the methylene chloride isremoved using a rotary evaporator, and the remaining material isdistilled using a short-path distillation apparatus to yieldN-ethylcarbamate of trans-homometanicotine product as a colorless liquidwhich has a boiling point of 170°-172° C. at 1 mm Hg. This product(0.012 mole) is dissolved in 50 mL concentrated aqueous hydrochloricacid, and the resulting mixture is refluxed overnight. The reactionmixture then is cooled. The resulting product is extracted four timeswith 20 mL quantities of chloroform, and the combined collectedfractions are dried over anhydrous sodium sulfate. Then, the chloroformis removed using a rotary evaporator, and the remaining material isdistilled under reduced pressure to yield the (E)-N-methyl-5-3-pyridinyl!-4-pentene-1-amine product as a colorless liquid which has aboiling point of 81°-82° C. at 4 mm Hg. That product can be converted toa fumarate salt, which has a melting point of 139°-140° C.

A representative compound, (E)-N-(2-propyl)-4-3-pyridynyl!-3-butene-1-amine, can be synthesized using the followingrepresentative procedure. (E)-4- 3-pyridynyl!-3-butene-1-amine (0.5millimole) is prepared according to the procedure of Heck, J. Org.Chem., Vol. 43, pp. 2947 (1978), combined with 2-iodopropane (0.525millimole) and potassium carbonate (1 millimole), and refluxed in 30 mLtetrahydrofiran for 36 hours. Then, the tetrahydrofuran is removed usinga rotary evaporator and 5 mL ethyl ether is added to the remainingresidue. Filtration followed by concentration on a rotary evaporatoryields a brown oil which can be purified by column chromatographyfollowed by distillation under reduced pressure (138°-140° C. at 0.25 mmHg ) to yield the (E)-N-(2-propyl)-4- 3-pyridynyl!-3-butene-1-amineproduct.

A representative compound, (E)-N-methyl-4-3-(5-aminopyridin)yl!-3-butene-1-amine, can be synthesized using thefollowing representative procedure. 5-Amino nicotine (1 millimole) isprepared according to the procedure of Rondahl, Acta. Pharm. Suec., Vol.14, pp. 113 (1977), combined with phthalic anhydride (1 millimole), andrefluxed in 3 mL toluene for 16 hours using a Dean-Stark trap. Thereaction mixture is cooled to ambient temperature and the toluene isremoved using a rotary evaporator. To the remaining residue is added 2mL methylene chloride, followed by dropwise addition of ethylchloroformate (1.1 millimole) under nitrogen atmosphere. The resultingmixture is refluxed for 8 hours, cooled to ambient temperature, andconcentrated on a rotary evaporator. The resulting viscous oil is heatedto 160° C. under vacuum for one hour, and then cooled to ambienttemperature. Then, 10 mL of a 10 percent aqueous solution of sodiumbicarbonate is added to the reaction mixture. That mixture then isextracted three times with 15 mL portions of chloroform. The combinedportions then are dried over anhydrous potassium carbonate. Filtrationfollowed by evaporation of chloroform yields a pale brown oil. This oilis dissolved in 1 mL tetrahydrofuran followed by 2 mL of a solution 2parts methyl amine in 3 parts water. This mixture is stirred for 10hours. Then, tetrahydrofuran and excess methyl amine are removed using arotary evaporator. Concentrated aqueous hydrochloric acid (5 mL) isadded to the reaction mixture followed by reflux for several hours. Theacidic solution, after cooling to ambient temperature, is extractedthree times with 10 mL portions of ethyl acetate. Then, the acidicsolution is basified using potassium carbonate and then sodiumhydroxide. The basic solution then is extracted four times with 10 mLportions of n-butyl alcohol. The combined extracts are dried overanhydrous magnesium sulfate. Filtration, followed by concentration on arotary evaporator vields the (E)-N-methyl-4-3-(5-aminopyridin)yl!-3-butene-1-amine product as a dark brown oil. Theproduct can be purified by column chromatography using achloroform:methanol:triethylamine (60:20:20) solvent system as aneluent.

The present invention relates to a method for providing prevention of aCNS disorder to a subject susceptible to such a disorder, and forproviding treatment to a subject suffering from a CNS disorder. Inparticular, the method comprises administering to a patient an amount ofa compound effective for providing some degree of prevention of theprogression of the CNS disorder (i.e., provide protective effects),amelioration of the symptoms of the CNS disorder, and amelioration ofthe reoccurrence of the CNS disorder. The method involves administeringan effective amount of a compound selected from the general formulaewhich are set forth hereinbefore. The present invention relates to apharmaceutical composition incorporating a compound selected from thegeneral formulae which are set forth hereinbefore. The compoundsnormally are not optically active. However, certain compounds canpossess substituent groups of a character so that those compoundspossess optical activity. Optically active compounds can be employed asracernic mixtures or as enantiomers. The compounds can be employed in afree base form or in a salt form (e.g., as pharmaceutically acceptablesalts, such as chloride, perchlorate, ascorbate, sulfate, tartrate,fumarate, citrate, malate, lactate or aspartate salts). CNS disorderswhich can be treated in accordance with the present invention includepresenile dementia (early onset Alzheimer's disease), senile dementia(dementia of the Alzheimer's type), Parkinsonism including Parkinson'sdisease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania,attention deficit disorder, anxiety, dyslexia, schizophrenia andTourette's syndrome.

The pharmaceutical composition also can include various other componentsas additives or adjuncts. Exemplary pharmaceutically acceptablecomponents or adjuncts which are employed in relevant circumstancesinclude antioxidants, free radical scavenging agents, peptides, growthfactors, antibiotics, bacteriostatic agents, immunosuppressives,buffering agents, anti-inflammatory agents, anti-pyretics, time releasebinders, anaesthetics, steroids and corticosteroids. Such components canprovide additional therapeutic benefit, act to affect the therapeuticaction of the pharmaceutical composition, or act towards preventing anypotential side effects which may be posed as a result of administrationof the pharmaceutical composition. In certain circumstances, a compoundof the present invention can be employed as part of a pharmaceuticalcomposition with other compounds intended to prevent or treat aparticular CNS disorder.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotionform), orally (e.g., in liquid form within a solvent such as an aqueousor non-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); or transdermally (e.g., usinga transdermal patch). Although it is possible to administer thecompounds in the form of a bulk active chemical, it is preferred topresent each compound in the form of a pharmaceutical composition orformulation for efficient and effective administration. Exemplarymethods for administering such compounds will be apparent to the skilledartisan. For example, the compounds can be administered in the form of atablet, a hard gelatin capsule or as a time release capsule. As anotherexample, the compounds can be delivered transdermally using the types ofpatch technologies available from Ciba-Geigy Corporation and AlzaCorporation. The administration of the pharmaceutical compositions ofthe present invention can be intermittent, or at a gradual, continuous,constant or controlled rate to a warm-blooded animal, such as a humanbeing. In addition, the time of day and the number of times per day thatthe pharmaceutical formulation is administered can vary. Administrationpreferably is such that the active ingredients of the pharmaceuticalformulation interact with receptor sites within the body of the subjectthat effect the functioning of the CNS.

The dose of the compound is that amount effective to prevent occurrenceof the symptoms of the disorder or to treat some symptoms of thedisorder from which the patient suffers. By "effective amount","therapeutic amount" or "effective dose" is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus, aneffective amount of compound is an amount sufficient to pass across theblood-brain barrier of the subject, to bind to relevant receptor sitesin the brain of the subject, and to elicit neuropharmacological effects(e.g., elicit neurotransmitter secretion, thus resulting in effectiveprevention or treatment of the disorder). Prevention of the disorder ismanifested by delaying the onset of the symptoms of the disorder.Treatment of the disorder is manifested by a decrease in the symptomsassociated with the disorder or an amelioration of the reoccurrence ofthe symptoms of the disorder.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 mg/24hr./patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 mg/24 hr./patient. In addition, administration of theeffective dose is such that the concentration of the compound within theplasma of the patient normally does not exceed 500 ng/ml, and frequentlydoes not exceed 100 ng/ml.

The compounds useful according to the method of the present inventionhave the ability to pass across the blood-brain barrier of the patient.As such, such compounds have the ability to enter the central nervoussystem of the patient. The log P values of typical compounds useful incarrying out-the present invention generally are greater than -0.5,often are greater than about 0, and frequently are greater than about0.5. The log P values of such typical compounds generally are less thanabout 3.0, often are less than about 2.5, and frequently are less thanabout 2.0. Log P values provide a measure of the ability of a compoundto pass across a diffusion barrier, such as a biological membrane. See,Hansch, et al., J. Med. Chem., Vol. 11, p. 1 (1968).

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic cholinergic receptors of the brain of the patient. Assuch, such compounds have the ability to express nicotinic pharmacology,and in particular, to act as nicotinic agonists. The receptor bindingconstants of typical compounds useful in carrying out the presentinvention generally exceed about 1 nM, often exceed about 200 nM, andfrequently exceed about 500 nM. The receptor binding constants of suchtypical compounds generally are less than about 10 uM, often are lessthan about 7 uM, and frequently are less than about 2 uM. Receptorbinding constants provide a measure of the ability of the compound tobind to half of the relevant receptor sites of certain brain cells ofthe patient. See, Cheng, et al., Biochem. Pharmacol., Vol. 22, pp.3099-3108 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyeliciting neurotransmitter secretion from nerve ending preparations(i.e., synaptosomes). As such, such compounds have the ability to causerelevant neurons to release or secrete acetylcholine, dopamine, andother neurotransmitters. Generally, typical compounds useful in carryingout the present invention provide for the secretion of dopamine inamounts of at least about 25 percent, often at least about 50 percent,and frequently at least about 75 percent, of that elicited by an equalmolar amount of S(-) nicotine. Certain compounds of the presentinvention can provide secretion of dopamine in an amount which canexceed that elicited by an equal molar amount of (S)-(-)-nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of nicotinic receptors of human muscle toany significant degree. In that regard, the compounds of the presentinvention demonstrate poor ability to cause isotopic rubidium ion fluxthrough nicotinic receptors in cell preparations derived from musclepreparations. Thus, such compounds exhibit receptor activation constantsor EC50 values (i.e., which provide a measure of the concentration ofcompound needed to activate half of the relevant receptor sites of theskeletal muscle of a patient) which are relatively high. Generally,typical compounds useful in carrying the present invention activateisotopic rubidium ion flux by less than 15 percent, often by less than10 percent, and frequently by less than 5 percent, of that elicited byan equal molar amount of (S)-(-)-nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects. By this is meant that a particular dose of compound resultingin prevention and/or treatment of a CNS disorder, is essentiallyineffective in eliciting activation of certain ganglionic-type nicotinicreceptors. This selectivity of the compounds of the present inventionagainst those receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue. As such, such compoundshave poor ability to cause isotopic rubidium ion flux through nicotinicreceptors in cell preparations derived from the adrenal gland.Generally, typical compounds useful in carrying the present inventionactivate isotopic rubidium ion flux by less than 15 percent, often byless than 10 percent, and frequently by less than 5 percent, of thatelicited by an equal molar amount of (S)-(-)-nicotine.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, andamelioration to some degree of the reoccurrence of CNS disorders.However, such effective amounts of those compounds are not sufficient toelicit any appreciable side effects, as demonstrated by increasedeffects relating to the cardiovascular system, and effects to skeletalmuscle. As such, administration of compounds of the present inventionprovides a therapeutic window in which treatment of certain CNSdisorders is provided, and side effects are avoided. That is, aneffective dose of a compound of the present invention is sufficient toprovide the desired effects upon the CNS, but is insufficient (i.e., isnot at a high enough level) to provide undesirable side effects.Preferably, effective administration of a compound of the presentinvention resulting in treatment of CNS disorders occurs uponadministration of less than 1/5, and often less than 1/10, that amountsufficient to cause any side effects to a significant degree.

The following example is provided in order to further illustrate variousembodiments of the invention but should not be construed as limiting thescope thereof. Unless otherwise noted, all parts and percentages are byweight.

EXAMPLE

Sample No. 1 is (E)-4-(5-pyrimidinyl)-3-butene-1-amine monofumarate(compound III monofumarate), which was prepared essentially inaccordance with the following techniques.

N-3-Butene-1-phthalimide (I):

This compound was prepared essentially in accordance with the techniquesdescribed in Heck, et al., J. Org. Chem., Vol. 43, pp. 2947-2949 (1978).

(E)-N- 4-(5-Pyrimidinyl)-3-butene-1-!phthalimide (II):

Under a nitrogen atmosphere, a mixture of I (28.20 g, 140 mmol),5-bromopyrimidine (21.63 g, 136 mmol), palladium(II) acetate (306 mg,1.4 mmol), tri-o-tolylphosphine (828 mg, 2.7 mmol), and triethylamine(27.54 g, 272 mmol) was stirred and heated at ˜110° C. for 27 h. Theprecipitated brown solids were slurried in water, filtered, anddissolved in hot N,N-dimethylfornamide (DMF) (75 mL). Charcoal (Darco®G-60, 1 g) was added and the mixture filtered through Celite® (1.8 g),washing the filter cake with hot DMF (10 mL). The filtrate was dilutedwith an equal volume of water and cooled at 5° C. for 15 h. The solidswere filtered, washed with water (2×25 mL) and dried, producing a beige,crystalline powder (28.55 g, 75.1%). Further purification, involving tworecrystallizations from DMF-water (1:1), followed by tworecrystallizations from toluene afforded compound II as a light beige,crystalline powder (18.94 g, 49.8%), mp 177°-178.5° C.

IR (KBr): 3445 (w), 3014 (w), 2951 (w), 1768 (m, C═O), 1703 (s, C═O),1650 (w, C═C), 1558 (m), 1433 (s), 1402 (s), 1367 (s), 1330 (m), 1057(m), 964 (m, trans C═C), 879 (m), 721 (s, 1,2-disubst. benzene), 717 (w,5-pyrimidinyl), 633 (w, 5-pyrimidinyl) cm⁻¹.

¹ H NMR (CDCl₃): δ 9.01 (s, 1H), 8.60 (s, 2H), 7.85 (m, 2H), 7.70 (m,2H), 6.35 (m, 2H), 3.85 (m, 2H), 2.63 (m, 2H).

¹³ C NMR(CDCl₃): δ 168.26, 157.21, 154.09, 134.07, 131.97, 131.37,130.69, 125.60, 123.33, 37.11, 32.49.

EI-MS: m/z (relative intensity) 279 (M⁺·, 5%), 160 (100%), 131 (43%),119 (45%), 104 (17%), 77 (31%), 65 (13%), 51 (11%).

HRMS: Calcd. for C₁₆ H₁₃ N₃ O₂ (M⁺·): m/z 279.0992. Found: 279.1008.

Anal. Calcd. for C₁₆ H₁₃ N₃ O₂ : C, 68.81; H, 4.69; N, 15.05. Found: C,68.68; H, 4.82; N, 14.94.

(E)-4-(5-Pyrimidinyl)-3-butene-1-amine (III):

Hydrazine hydrate (2.69 g, 53.7 mmol, 99%) was added to a mixture of II(6.00 g, 21.5 mmol) and methanol (100 mL), and the mixture was stirredat ambient temperature for 27 h. The white suspension was diluted with1M NaOH solution (400 mL) and extracted with chloroform (5×100 mL). Thechloroform extracts were combined, dried (Na₂ SO₄), filtered, andconcentrated by rotary evaporation. The residue was vacuum dried 5 h at55° C. to give (E)-4-(5-pyrimidinyl)-3-butene-1-amine (III) as a lightyellow oil (2.95 g, 92.2%), which was used without further purification.

IR (film): 3345 (br, N--H), 1655 (m, C═C), 1560 (s), 1490 (s), 1440 (s),1415 (s), 1390 (m), 1317 (s), 1190 (m), 968 (m, trans C═C), 721 (s,5-pyrimidinyl), 636 (m, 5-pyrimidinyl) cm⁻¹.

¹ H NMR (CDCl₃): δ 9.13 (s, 1H), 8.68 (s, 2H), 6.38 (m, 2H), 2.84 (t,2H, J=7 Hz), 2.40 (m, 2H), 1.26 (br s, 2H).

¹³ C NMR (CDCl₃): δ 157.04, 153.96, 133.16, 130.92, 124.82, 41.36,37.44.

EI-MS: m/z (relative intensity) 148 (M⁺· -1, 0.1%), 132 (1%), 120(100%), 93 (31%), 66 (40%), 51 (11%), 44 (14%).

The monofumarate of III was prepared by adding a warm solution offumaric acid (156 mg, 1.34 mmol) in ethanol (5 mL) to a warm solution ofIII (100 mg, 0.67 mmol) in ethanol (3 mL). The mixture was concentratedby rotary evaporation, and the slightly yellow solids wererecrystallized from ethanol-ether (1:1). The solids were filtered,washed with ethanol, ether, and vacuum dried at 50° C. for 24 h,affording the monofumarate as a white, crystalline powder (63.8 mg,35.9%), mp 160°-161.5° C.

IR (KBr): 3300-2300 (br, s, amine-carboxylate), 1705 (s, C═O), 1664 (s),1606 (s, C═C), 1556 (s), 1409 (s, fumarate), 1254 (m), 1186 (m), 981 (m,trans C═C), 852 (m), 796 (m), 723 (w, 5-pyrimidinyl), 648 (m, fumarate),631 (m, 5-pyrimidinyl) cm⁻¹.

¹ H NMR (D₂ O): δ 9.00 (s, 1H), 8.84 (s, 2H), 6.69 (s, 2H), 6.63 (d, 1H,J=16.4 Hz), 6.52 and 6.46, (dt, 1H, J=16.1, 6.8 Hz), 3.20 (m, 2H), 2.72(m, 2H).

¹³ C NMR (D₂ O): δ 171.45, 154.10, 134.63, 131.04, 130.23, 126.05,38.40, 30.33.

Anal. Calcd. for C₈ H₁₁ N₃.C₄ H₄ O₄ : C, 54.33; H, 5.70; N, 15.84.Found: C, 54.24; H, 5.75: N, 15.65.

Sample No. 2 is (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine(compound VI), which was prepared essentially in accordance with thefollowing techniques.

(E)-N-tert-Butyloxycarbonyl-4-(5-pyrimidinyl)-3-butene-1-amine (IV):

A solution of di-tert-butyl dicarbonate (2.66 g, 12.2 mmol) in methylenechloride (10 mL) was added dropwise over 5 min to a stirring solution of(E)-4-(5-pyrimidinyl)-3-butene-1-amine (III) (1.70 g, 11.4 mmol) inmethylene chloride at 0° C. The yellow solution was stirred at 0° C. for15 min and at ambient temperature for 22 h. Concentration by rotaryevaporation, followed by vacuum drying at 30° C. for 15 h afforded ayellow oil. The oil was chromatographed on silica gel (165 g), elutingfirst with ethyl acetate to remove impurities. Elution withchloroform-methanol (2:1) afforded the product which wasre-chromatographed eluting with ethyl acetate. Selected fractions werecombined in chloroform and concentrated by rotary evaporation. Theresidue was vacuum dried at 35° C. for 48 h to give compound IV as alight yellow oil (2.56 g, 90.1%), which crystallized upon cooling,affording a light yellow, crystalline solid, mp 54°-55.5° C.

IR (KBr): 3030 (w), 2990 (w), 2980 (w), 2965 (w), 2935 (w), 3298 (s,amide N--H), 1712 (s, carbamate C═O), 1657 (w, C═C), 1560 (s), 1535 (s,amide N--H), 1433 (s), 1414 (s), 1367 (s, tert-butyl), 1275 (s, amideN--H), 1246 (s, ester C--O), 1174 (s, ester C--O), 1149 (s), 1111 (m),987 (m), 966 (m trans C═C), 723 (w, 5-pyrimidinyl), 636 (m,5-pyrimidinyl) cm⁻¹.

¹ H NMR (CDCl₃): δ 9.05 (s, 1H), 8.70 (s, 2H), 6.37 (m, 2H), 4.59 (br s,1H), 3.30 (m, 2H), 2.43 (m, 2H), 1.46 (s, 9H).

¹³ C NMR (CDCl₃): δ 157.34, 156.83, 155.84, 154.18, 153.79, 132.24,130.75, 125.15, 79.42, 39.64, 34.05, 28.56, 28.20.

EI-MS: m/z (relative intensity) 249 (M⁺·, 0.1%), 193 (15%), 176 (24%),132 (16%), 120 (79%), 119 (85%), 93 (19%), 65 (24%), 57 (100%).

Anal. Calcd. for C₁₃ H₁₉ N₃ O₂ : C, 62.62; H, 7.68; N, 16.86. Found: C,62.61; H, 7.62; N, 16.78.

(E)-N-Methyl-N-tert-Butyloxycarbonyl-4-(5-pyrimidinyl)-3-butene-1-amine(V):

Under a nitrogen atmosphere, sodium hydride (0.78 g, 19.5 mmol, 60%dispersion in oil) was added to a stirring solution of IV (0.50 g, 2.0mmol), 1,2-dimethoxyethane (20 mL), DMF (25 mL), and a trace ofdiisopropylamine. The mixture was stirred at ambient temperature for 45min, and a solution of iodomethane (2.59 g, 18.3 mmol) in1,2-dimethoxyethane (5 mL) was added. The mixture was stirred at ambienttemperature for 3 days, cooled, and water (25 mL) was added dropwise.The mixture was diluted with water (200 mL) and extracted withchloroform (7×50 mL). All chloroform extracts were combined, dried (Na₂SO₄), filtered, and concentrated by rotary evaporation. The residue wasdried under high vacuum at ambient temperature to give a red-brown oil.The oil was chromatographed on silica gel (50 g), eluting with ethylacetate. Selected fractions were combined, concentrated by rotaryevaporation, and dried under high vacuum at ambient temperature to givecompound V as a light yellow oil (0.40 g, 76.1%).

IR (film): 3650-3200 (br, w), 2980 (m), 2940 (m), 1697 (s, carbamateC═O), 1556 (s), 1484 (s), 1452 (s), 1420 (s, N--CH₃), 1411 (s,tert-butyl), 1394 (s, tert-butyl), 1369 (s), 1304 (m), 1249 (m, esterC--O), 1218 (m), 1163 (s, ester C--O), 1136 (s), 972 (m, trans C═C), 883(m), 774 (m), 721 (m, 5-pyrimidinyl), 631 (m, 5-pyrimidinyl) cm⁻¹.

¹ H NMR (CDCl₃): δ 9.01 (s, 1H), 8.63 (s, 2H), 6.31 (m, 2H), 3.32 (m,2H), 2.82 (s, 3H), 2.44 (m, 2H), 1.39 (s, 9H).

¹³ C NMR (CDCl₃): δ 157.06, 155.70, 153.95, 132.49, 130.94, 124.73,79.51, 34.38, 28.45.

EI-MS: m/z (relative intensity) 263 (M⁺·, 0.3%), 207 (5%), 190 (7%), 144(24%), 133 (9%), 120 (39%), 93 (13%), 88 (15%), 65 (11%), 57 (100%), 44(89%).

HRMS: Calcd. for C₁₄ H₂₁ N₃ O₂ (M⁺·): m/z 263.1634. Found: 263.1643.

(E)-N-Methyl-4-(5-pyrimidinyl)-3-butene-1-amine (VI):

Under a nitrogen atmosphere, iodotrimethylsilane (0.50 g, 2.5 mmol) wasadded dropwise, at ambient temperature, to a stirring solution of V(0.33 g, 1.2 mmol) in chloroform (20 mL). The red-brown mixture wasstirred 30 min and methanol (20 mL) was added. The mixture was stirred 1h and concentrated by rotary evaporation. The residue was basified with1M NaOH solution (25 mL) and extracted with chloroform (7×25 mL). Thechloroform extracts were combined, dried (Na₂ SO₄) and concentrated byrotary evaporation, affording a brown oil. The oil was chromatographedon silica gel (35 g), eluting with methanol-ammonium hydroxide (10:1).Selected fractions were combined, vacuum dried at 45° C. for 3 h,affording (E)-N-methyl-N-4-(5-pyrimidinyl)-3-butene-1-amine (VI) as abrownish-yellow oil (0.12 g, 59.6%).

IR (film): 3148 (br, s, N--H), 1653 (s, C═C), 1560 (s), 1473 (m), 1435(s), 1414 (s, N--CH₃), 970 (m, trans C═C), 721 (s, 5-pyrimidinyl), 636(s, 5-pyrimidinyl) cm⁻¹.

¹ H NMR (CDCl₃): δ 9.02 (s, 1H), 8.68 (s, 2H), 6.37 (m, 2H), 2.76 (t,2H, J=6.8 Hz) 2.46 (m, 5H, including a N--CH₃ singlet), 1.65 (br s, 1H).

¹³ C NMR (CDCl₃): δ 157.09, 154.01, 132.99, 130.90, 124.81, 50.76,36.06, 33.35.

EI-MS: m/z (relative intensity) 146 (0.3%), 132 (0.4%), 120 (22%), 93(4%), 65 (4%), 44 (100%).

HRMS: Calcd. for C₇ H₈ N₂ (M⁺·- 44): m/z 120.0676. Found: 120.0687.

Sample No. 3 is (E)-4- 3-(5-methoxypyridin)yl!-3-butene-1-aminemonofumarate (compound IX monofumarate), which was prepared essentiallyin accordance with the following techniques.

3-Bromo-5-methoxypyridine (VII)

This compound was prepared essentially in accordance with the techniquesdescribed in Comins et al., J. Org. Chem., Vol. 55, pp. 69-73 (1990

(E)-N4- 3-(5-methoxypyridin)yl!-3-butene-1-phthalimide (VIII):

Under a nitrogen atmosphere, a mixture of N-3-butene-1-phthalimide (I)(5.51 g, 27.4 mmol), 3-bromo-5-methoxypyridine (VII) (5.00 g, 26.6mmol), palladium(II) acetate (59.7 mg, 0.27 mmol), tri-o-tolylphosphine(162 mg, 0.53 mmol), and triethylamine (5.38 g, 53.2 mmol) was stirredand heated at ˜100° C. for 21 h. The precipitated brown solids wereslurried in water, filtered, and dissolved in hot DMF (30 mL). Themixture was filtered through Celite® (1 g), washing the filter cake withhot DMF (10 mL). The filtrate was diluted with an equal volume of waterand cooled at 5° C. for 15 h. The solids wvere filtered, washed withwater (2×10 mL), cold ethanol (10 mL), and dried, producing a beige,crystalline powder (7.79 g, 95.0%). Further purification, involving tworecrystallizations from DMF-water (1:1) afforded compound VIII as alight beige, crystalline powder (5.36 g, 65.4%), mp 148°-151° C. Ananalytical sample was recrystallized from toluene, affording a lightbeige, crystalline powder, mp 148°-151.5° C.

IR (KBr): 3440 (w), 3040 (m), 2960 (s), 2940 (s), 2825 (w), 1766 (m,C═O), 1700 (s, C═O), 1654 (m, C═C), 1580 (m, pyridinyl), 1455 (s), 1420(s), 1320 (m), 1190 (m), 1000 (s), 973 (s, trans C═C), 867 (s,3,5-disubst. pyridine), 723 (s, 1,2-disubst. benzene), 703 (s,3,5-disubst. pyridine) cm⁻¹.

¹ H NMR(CDCl₃): δ 8.14 (s, 1H), 8.08 (s, 1H), 7.82 (m, 2H), 7.69 (m,2H), 7.10 (dd, 1H, J=2.4, 2.0 Hz), 6.38 (d, 1H, J=16.1 Hz), 6.25 and6.20 (dt, 1H, J=15.9, 6.8 Hz), 3.84 (t, 5H, including an O--CH₃ singlet,J=7.1 Hz), 2.62 (dq, 2H, J=7.1, 1.0 Hz).

¹³ C NMR (CDCl₃): δ 168.27, 155.73, 140.72, 136.45, 133.96, 132.05,129.00, 123.26, 116.80, 55.52, 37.34, 32.30.

EI-MS: m/z (relative intensity) 308 (M⁺·, 13%), 160 (100%), 148 (8%),133 (10%), 105(8%), 77 (15%).

Anal. Calcd. for C₁₈ H₁₆ N₂ O₃ : C, 70.12; H, 5.23; N, 9.09. Found: C,70.34; H, 5.29; N, 9.00.

(E)-4- 3-(5-methoxypyridin)yl!-3-butene-1-amine (IX):

Hydrazine hydrate (245 mg, 4.90 mmol, 99%) was added to a mixture ofVIII (500 mg, 1.62 mmol) and methanol (20 mL), and the mixture wasstirred at ambient temperature for 20 h. The gray suspension was dilutedwith 1M NaOH solution (190 mL) and extracted with chloroform (5×25 mL).The chloroform extracts were combined, dried (Na₂ SO₄), filtered, andconcentrated by rotary evaporation. The crude product (287 mg) wasfurther purified by vacuum distillation, affording compound IX (183 mg,62.3%) as a light yellow oil, bp 110° C. at 0.05 mm Hg.

IR (film): 3350 (br, s), 3035 (s), 2940 (s), 2840 (m), 1585 (s), 1460(s), 1425 (s), 1320 (s), 1295 (s, ArO--CH₃), 1185 (m), 1160 (m), 1050(m), 1020 (sh), 965 (s, trans C═C), 885 (m 3,5-disubst. pyridine), 820(w), 710 (m, 3,5-disubst. pyridine).

¹ H NMR (CDCl₃): δ 8.16 (d, 1H, J=2.0 Hz), 8.13 (d, 1H, J 2.9 Hz), 7.14(dd, 1H, J=2.6, 2.0 Hz), 6.41 (d, 1H, J=15.9 Hz), 6.27 and 6.22 (dt, 1H,J=15.9, 7.1 Hz), 3.84 (3H), 2.84 (t, 2H, J=6.6 Hz), 2.36 (dq, 2H, J=6.6,1.0 Hz).

¹³ C NMR (CDCl₃): 155.79, 140.70, 136.24, 133.72, 130.79, 128.27,116.91, 55.57, 37.29, 29.70.

EI-MS: m/z (relative intensity) 178 (M⁺·, 0.4%), 149 (88%), 148 (100%),133 (12%), 105 (9%), 78 (10%).

The monofumarate of IX was prepared by adding a warm solution of fumaricacid (131 mg, 1.12 mmol) in 2-propanol (15 mL) to compound IX (166 mg,0.93 mmol). After stirring 30 min, the solution was concentrated byrotary evaporation to a white powder. The crude product wasrecrystallized from 2-propanol, and the mixture was stored at ambienttemperature for 15 h. The solids were filtered, washed with cold2-propanol, ether, and vacuum dried at 50° C. for 6 h, affording themonof umarate as a white, crystalline powder (177 mg, 64.6%), mp151°-153° C.

IR (KBr): 3300-2400 (br, s, amine-carboxylate), 1700 (s, C═O), 1630 (s,C═O), 1570 (sh), 1535 (m), 1460 (m), 1435 (m), 1290 (s, ArO--CH₃), 1158(m), 1040 (m), 982 (s, trans C═C), 875 (m, 3,5-disubst. pyridine), 793(m), 705 (m, 3,5-disubst. pyridine), 652 (m).

¹ H NMR (D₂ O): δ 8.31 (s, 1H), 8.25 (s, 1H), 7.85 (s, 1H), 6.68 (d, 1H,J=16.1 Hz), 6.57 (s, 2H), 6.53 and 6.48 (dt, 1H, J=15.9, 7.1 Hz), 3.98(s, 3H), 3.21 (t, 2H, J=7.1 Hz), 2.68 (q, 2H, J=7.1 Hz).

¹³ C NMR (D₂ O): δ 172.93, 156.77, 136.17, 135.62, 134.90, 131.81,130.25, 128.04, 122.44, 56.31, 38.54, 30.14.

Anal. Calcd. for C₁₀ H₁₄ N₂ O.C₄ H₄ O₄ : C, 57.14; H, 6.16; N, 9.52.Found: C, 56.91; H, 6.18; N, 9.51.

Sample No. 4 is N-Methyl-4-(3-pyridinyl)-3-butyne-1-amine which wasprepared essentially in accordance with the following techniques.

1,1-Dibromo-2-(3-pyridinyl)-ethylene (X)

Tetrabromomethane (24.82 g, 0.747 mole) and triphenylphosphine (39.17 g,0.149 mole) were stirred together in dry methylene chloride (100 mL) for5 min. at 0° C. under a nitrogen atmosphere. To this mixture was addeddropwise pyridine 3-carboxaldehyde (4 g, 0.0373 mole). The solution wasthen stirred for 45 min. at ambient temperature. The reaction mixturewas extracted with aqueous 6N hydrochloric acid (3×25 mL), the aqueouslayer basified with solid sodium bicarbonate to pH 8-9 and extractedwith chloroform (4×25 mL). The combined organic liquours were dried overanhydrous sodium sulfate, filtered and concentrated on a rotaryevaporator to give a dark colored syrup. The crude product waschromatographed on silica gel (70-230 mesh) with chloroform:methanol(95:5) as eluant, to afford a light yellow solid (5.0 g, 70%) whichrapidly turned dark on standing.

¹ H NMR(CDCl₃) δ 8.65 (s, H), 8.58 (d, 1H), 8.00 (d, 1H), 7.45 (s, 1H),7.22-7.36 (m,1H).

Anal. calcd. for C₇ H₄ NBr₂ : C, 31.94; H, 1.90; N, 5.32; Br, 60.84.Found: C, 32.11; H, 2.03; N, 5.50; Br, 60.99.

4-(3-Pyridinyl)-3-butyne-1-ol (XI)

To dry THF (10 mL) contained in a 50 mL round-bottomed flask fixed witha nitrogen gas balloon was added X (2.5 g, 0.01 mole). The flask wascooled to -78° C. in an acetone-dry ice bath, and n-butyl lithium in THF(22 mL of a 2.5 molar solution in THF) was added dropwise via a syringduring constant stirring. After addition, the solution was stirred for 1hour. The reaction mixture temperature was then adjusted to -60° C. andethylene oxide (1 mL) was added in one portion, and the reaction wasallowed to warm to ambient temperature with stirring. The resultingreaction mixture was quenched with water (10 mL) and extracted withchloroform (3×25 mL), the combined organic liquors dried over anhydroussodium sulfate, filtered and concentrated on a rotary evaporator underreduced pressure. The resulting oil was chromatographed on silica gel toafford the product as a light brown liquid (590 mg, 40%).

¹ H NMR (CDCl₃) δ 8.71 (s, 1H), 8.49 (d, 1H), 7.68 (d, 1H) 7.29-7.36 (m,1H), 3.92 (t, 2H), 2.80(m, 5H).

Anal. calcd. for C₉ H₉ NO: C, 73.46; H, 6.12; N, 9.52. Found: C, 73.61;H, 6.31; N, 9.66.

Methanesulfonate ester of 4-(3-Pyridinyl)-3-butyne-1-ol (XII)

In dry methylene chloride (2 mL) was dissolved XI (0.15 g, 1.0 mmole),and to this solution was added triethylamine (0.184 ml, 1.3 mmole). Thereaction was stirred overnight under nitrogen atmosphere. The mixturewas cooled to 4° C. and methane sulfonyl chloride (0.15 g, 1.3 mmole)wvas added. The reaction mixture was then poured over ice/water (10 mL)and the resulting mixture stirred for 5 min. To this mixture was addedsaturated aqueous sodium bicarbonate solution (5 mL) chilled to 4° C.,and the mixture stirred for 30 min., then extracted with chloroform(4×10 mL). The combined organic fractions were dried over anhydroussodium sulfate, filtered and the volume concentrated on a rotaryevaporator. The product was further purified using gel chromatography,eluting with a chloroform: methanol mixture containing 1% triethylamine.Yield of XII is 0.218 g (about 97%).

¹ H NMR (CDCl₃) δ 8.59 (s, 1H), 7.62 (d, 1H), 7.18-7.22 (m, 1H), 4.31(t, 2H), 3.00 (s, 3H), 2.80 (t, 2H).

N-Methyl-4-(3-pyridinyl)-3-butyne-1-amine (XIII)

An aqueous methylamine solution (5 mL, 40%, 58.7 mmole) was mixed withXII (200 mg, 0.08 mmole) and stirred for 3 hr. in a sealed tube at 45°C. After the reaction was complete, water (10 mL) was added to thecooled reaction mixture, and the reaction mixture was extracted withchloroform (10×5 mL). The combined organic extracts were dried overanhydrous sodium sulfate, filtered and concentrated. The residueobtained was chromatographed on a silica gel column usingmethanol:chloroform (1:9) and then with a chloroform: methanol mixturecontaining 1% triethylamine as eluent. About 70 mg of XIII was obtainedas a slightly yellow syrup, which was distilled at 110°-112° C., 0.04 mmHg. XIII was converted to its mono fumarate salt form, which exhibits amelting point of 103°-104° C.

Free base. ¹ H NMR (CDCl₃) δ 8.61 (s, 1H), 8.48 (d, 1H), 7.62 (d, 1H),7.20 (t, 1H), 2.82 (t, 2H), 2.61 (t, 2H), 2.33 (s, 3H), 1.4 (br s, 1H).

Fumarate salt. ¹ H NMR (D₂ O) δ 8.51 (s, 1H), 8.89 (d, 1H), 7.91 (d,1H), 7.40 (m, 1H), 6.28 (s, 2H), 3.20 (t, 2H), 2.80 (t, 2H), 2.62 (s,3H).

¹³ C NMR (D₂ O) δ 164.5, 151.8, 148.0, 146.0, 138.8, 128.2, 124.5, 93.0,82.3, 50.4, 36.2, 20.1.

Anal. calcd. for C₁₄ H₁₆ N₂ O₄ : C, 60.86; H, 5.70; N, 10.14. Found: C,60.84; H, 5.72; N, 10.23.

Sample No. 5 is (Z)-metanicotine which was prepared essentially inaccordance with the following techniques.

(Z)-Metanicotine (XIV)

Into a hydrogenation bottle together with methanol (20 mL), glacialacetic acid (1 mL) and a catalytic amount of quinoline was placed XIIIfree base (200 mg, 1.25 mmole). Lindlar's catalyst (palladium/calciumcarbonate poisoned with lead) (60 mg) was added and the mixturehydrogenated at 50 psig in a Parr reaction apparatus overnight atambient temperature. The catalyst was filtered off, the resultingsolution basified with aqueous sodium hydroxide (50% w/v) to a pH 8-9,and then extracted with chloroform (3×25 mL). The combined organicliquors were concentrated on a rotary evaporator, and the residuechromatographed on 60-230 mesh silica gel, using chloroform:methanol:triethylamine (90:10:1) as eluent, to afford XIV as a colorless oil atabout 100% yield. XIV is converted to its mono fumarate salt, which hasa melting point of 117°-118° C.

Free-base. ¹ H NMR (CDCl₃) δ 8.56 (s, 1H), 8.42 (d, 1H), 7.60 (d, 1H),7.22 (m, 1H), 6.81 (m, 1H), 6.51 (d, 1H), 2.79 (t, 2H), 2.52 (m, 2H),2.41 (s, 3m).

Difumarate salt. ¹ H NMR (D₂ O) δ 8.48 (br s, 2H), 8.10 (d, 1H),7.75-7.63 (m, 1H), 6.52 (d, 1H), 6.40 (s, 1H), 5.85-5.78 (m, 1H), 3.00(t, 2H), 2.51 (m, 5H).

Anal. calcd. for C₁₀ H₁₄ N₂.2C₄ H₄ O₄ : C, 54.82; H, 5.58; N, 7.10.Found: C, 54.47; H, 5.68; N, 6.98.

Sample No. 6 is (E)-N-methyl-4- 3-(6-methylpyrindin)yl!-3-butene-1-aminewhich was prepared essentially in accordance with the followingtechniques.

6-Methylmyosmine (XV)

Sodium hydride (60% in oil) (1.9 g, 0.079 mole) was placed in a 250 mLtwo-necked round bottom flask and washed with dry THF (50 mL). A furtheraliquot of dry THF (100 mL) was added followed by a solution ofN-vinylpyrrolidone (4.7 g, 0.04 mole) in dry THF (30 mL), and themixture stirred for 30 min. at ambient temperature. A solution of ethyl6-methylnicotinate (5.0 g, 0.033 mole) in dry THF (20 mL) was then addeddropwise over 10 min., during which time evolution of hydrogen occurred.The reaction was flushed with nitrogen, and the mixture refluxed for 6hr. After cooling, aqueous hydrochloric acid (6N, 25 mL) was added andthe THF removed by rotory evaporation under reduced pressure. A furthervolume of aqueous hydrochloric acid (6N, 20 mL) was added and themixture refluxed overnight. On cooling, the mixture was basified withaqueous sodium hydroxide (50% w/v) to pH 8-9, and XV was extracted withchloroform (5×20 mL). The combined organic liquours were dried overanhydrous sodium sulfate, filtered and the solvent evaporated to affordXV, which was crystallized from methanol as a tan solid (4.45 g, 84%).

¹ H NMR (CDCl₃) δ 8.82 (s, 1H), 8.15 (d, 1H), 7.20 (d, 1H), 4.12 (t,2H), 2.98 (t, 2H), 2.80 (s, 3H). 2.00 (m, 2H).

¹³ C NMR (CDCl₃) δ 172.5, 160.08, 148.1, 135.01, 122.7, 61.5, 34.8,24.2, 22.2.

Anal. calcd. for C₁₀ H₁₂ N₂ : C, 75.00, H, 7.50; N, 17.50. Found: C,74.94; H, 7.51; N, 17.47.

(+/-)-6-Methylnomicotine (XVI)

Into a round bottom flask was placed XV (3.0 g, 0.018 mole), methanol(20 mL) and glacial acetic acid (4 mL). The mixture was cooled to -78°C. in a dry ice-acetone bath, and sodium borohydride (1.332 g, 0.36mole) was added over 30 min. After addition, the reaction mixture wasallowed to warm to ambient temperature, and stirred for 1 hr. Themethanol then was removed on a rotary evaporator under reduced pressureand the residue was basified with aqueous sodium hydroxide (50% w/v) topH 8-9. The aqueous solution was extracted with chloroform (5×25 mL) andthe combined organic liquors dried over anhydrous sodium sulfate,filtered and evaporated on a rotary evaporator to afford XVI as a darkbrown liquid, which was distilled at 4 mm Hg to yield a clear, colorlessliquid (b.p. is 113°-114° C., 4 mm Hg) (2.43 g, 80%).

¹ H NMR (CDCl₃) δ 8.42 (s, 1H), 7.60 (d, 1H), 7.10 (d, 1H), 4.15 (t,1H), 3.12 (m, 1H), 3.00 (m, 1H), 2.30 (s, 3H), 2.20-2.00 (m, 3H),2.00-1.98 (m, 2H),

HClO₄ salt ¹ H NMR (D₂ O) δ 8.62 (s, 1H), 8.40 (d, 1H), 7.81 (d, 1H),3.58 (t, 2H), 2.78 (s, 3H), 2.40-2.20 (m, 4H).

Anal. calcd. for C₁₀ H₁₆ N₂ Cl₂ O₈ : C, 33.05; H, 4.40; N, 7.71; Cl,19.55. Found: C, 33.16; H, 4.46; N, 7.64; Cl, 19.43.

(+/-)-6-Methylnicotine (XVII)

Into a round bottom flask was placed XVI (2.0 g), and formaldehyde (37%w/v in water, 20 mL) and formic acid (95-97% w/v, 45 mL), both a 0° C.,were added. The mixture then was refluxed under nitrogen for 8 hr. Thecooled reaction mixture was basified with aqueous sodium hydroxide (50%w.v) to pH 8-9, and the solution extracted with chloroform (5×25 mL).The combined organic liquors were dried over anhydrous sodium sulfate,filtered and evaporated; and the resulting oil distilled under reducedpressure to afford XVII as a clear odorless oil (b.p. 107° C. at 3 mmHg, 92% yield).

¹ H NMR (CDCl₃) δ 8.40 (s, 1H), 7.60 (d, 1H), 7.12 (d, 1H), 3.15 (t,1H), 3.00 (t, 1H), 2.56 (s, 3H) 2.40-2.20 (m, 1H), 2.18-2.08 (m, 4H),2.00-1.92 (m, 1H), 1.80-1.60 (m, 2H).

HClO₄ salt. Anal. calcd. for C₁₁ H₁₈ N₂ Cl₂ O₈ : C, 35.01; H, 4.77; N,7.42; Cl, 18.83. Found: C, 35.12; H, 4.85; N, 7.37; Cl, 18.76.

N-Ethylcarbamate of (+/-)-6-methylmetanicotine (XVIII)

To a stirred solution of XVII (3.0 g, 0.017 mole) in methylene chloride(25 mL) under nitrogne atmosphere was added dropwise a solution ofethylchloroformate (2.40 g) in methylene chloride (10 mL) at ambienttemperature. The mixture was refluxed for 4 hr. After evaporation ofsolvent on a rotary evaporator under reduced pressure, the resulting oilwas vacuum distilled to give XVIII as a thick viscous liquid (b.p.172°-175° C., 4 mm Hg), which was further purified by silica columnchromatography, to yield about 3 g of XVIII (70% yield).

1H NMR (CDCl₃) δ 8.40 (s, 1H), 7.61 (d, 1H), 7.08 (d, 1H), 6.60 (d, 1H),6.08-6.00 (m, 1H), 4.18 (q, 2H), 3.40 (m, 2H), 2.91 (s, 3H), 2.60-2.42(m, 5H), 1.22 (t, 3H).

(E)-N-methyl-4- 3-(6-methylpyrindin)yl!-3-butene-1-amine (XIX)

Into a round bottom flask was placed XVIII (3.0 g, 0.012 mole), andconcentrated hydrochloric acid (15 mL) was added. The mixture wasrefluxed overnight, and the resulting solution basified with aqueoussodium hydroxide (50% w/v) to pH 8-9. The solution was extracted withchloroform (4×25 mL), the combined organic liquors dried over anhydroussodium carbonate. filtered, and the solvent evaporated to afford an oil.Vacuum distillation of the oil afforded XIX as a clear, colorless liquid(b.p. 80° C. at 0.2 mm Hg, 78% yield). XIX then was provided in the formof a monofumarate salt, m.p. 134°-135° C.

Difumarate salt. ¹ H NMR (DMSO-d₆) δ 8.42 (s, 1H), 7.76 (d, 1H), 7.20(d, 1H), 6.52-6.24 (m, 4H), 3.00 (t, 2H), 2.60-2.00 (m, 3H).

Anal. Calcd. for C₁₁ H₁₆ N₂.2C₄ H₄ O₄ : C, 55.88; H, 5.88; N, 6.86.Found: C, 55.72; H, 5.93; N, 6.83.

Sample No. 7 is N-methyl-(3-pyridinyl)-butane-1-amine, which wasprepared essentially in accordance with the following techniques.

(E)-Metanicotine (0.4 g, 2.46 mmole) was dissolved in a mixture ofmethanol (20 mL) and glacial acetic acid (1 mL) and 5% Pd-C catalyst (30mg) was added. The mixture was hydrogenated at 50 psig hydrogen for 2hr. The reaction mixture then was filtered and the solvent removed on arotary evaporator. To the residue was added water (5 mL) and the aqueoussolution basified to pH 8-9 with 40% aqueous sodium hydroxide. Themixture then was extracted with chloroform (5×10 mL), and the combinedorganic liquors dried over potassium carbonate, filtered and solvent wasevaporated under reduced pressure on a rotovaporator. The resulting oilthen was provided in the form of a difurnarate salt, melting point being115°-116° C.

Free base. ¹ H NMR (CDCl₃) δ 8.42 (m, 2H), 7.50 (d, 1H), 7.20 (m, 1H),2.64-2.58 (m, 4H), 2.40 (s, 3H) 2.78-2.60 (m, 2H), 2.42-2.59 (m, 2H),1.22 (broad s, 1H).

Difumarate salt. ¹ H NMR (D₂ O) δ 8.64 (d, 2H), 8.43 (d, 1H), 8.00 (m,1H), 6.62 (s, 4H), 3.24 (t, 2H), 2.90 (t, 2H), 2.70 (s, 3H), 1.81-1.69(m, 4H).

Anal. calcd. for C₁₀ H₁₆ N₂.2C₄ H₄ O₄.1/2H₂ O: C, 53.33; H, 6.17; N,6.91. Found: C, 53.33; H, 6.06; N, 7.07.

Sample No. 8 is (E)-metanicotine which was provided generally using thetechniques set forth by Laforge, J.A.C.S., Vol. 50, p. 2477 (1928).

For comparison purposes, Sample No. C-1 was provided. This sample is(S)-(-)-nicotine, which has been reported to have demonstrated apositive effect towards the treatment of various CNS disorders.

Determination of binding of compounds to relevant receptor sites

Rats (Sprague-Dawley) were maintained on a 12 hour light/dark cycle andwere allowed free access to water and food supplied by Wayne Lab Blox,Madison, Wis. Animals used in the present studies weighed 200 to 250 g.Brain membrane preparations were obtained from brain tissue of eithermales or females.

Rats were killed by decapitation following anesthesia with 70% CO₂.Brains were removed and placed on an ice-cold platform. The cerebellumwas removed and the remaining tissue was placed in 10 volumes(weight:volume) of ice-cold buffer (Krebs-Ringers HEPES: NaCl, 118 mM;KCl, 4.8 mM; CaCl₂, 2.5 mM; MgSO₄, 1.2 mM; HEPES, 20 mM; pH to 7.5 withNaOH) and homogenized with a glass-Teflon tissue grinder. The resultinghomogenate was centrifuged at 18,000×g for 20 min. and the resultingpellet was resuspended in 20 volumes of water. After 60 min. incubationat 4° C., a new pellet was collected by centrifugation at 18,000×g for20 min. After resuspension in 10 volumes of buffer, a new final pelletwas again collected by centrifugation at 18,000×g for 20 min. Prior toeach centrifugation step, the suspension was incubated at 37° C. for 5min. to promote hydrolysis of endogenous acetylcholine. The final pelletwas overlayered with buffer and stored at -70° C. On the day of theassay, that pellet was thawed, resuspended in buffer and centrifuged at18,000×g for 20 min. The pellet obtained was resuspended in buffer to afinal concentration of approximately 5 mg protein/ml. Protein wasdetermined by the method of Lowry et al., J. Biol. Chem., Vol. 193, pp.265-275 (1951), using bovine serum albumin as the standard.

The binding of L- ³ H!nicotine was measured using a modification of themethod of Romano et al., Science, Vol. 210, pp. 647-650 (1980) asdescribed previously by Marks et al., Mol. Pharmacol., Vol. 30, pp.427-436 (1986). The L- ³ H!nicotine used in all experiments was purifiedchromatographically by the method of Romm, et al., Life Sci., Vol. 46,pp. 935-943 (1990). The binding of L- ³ H!nicotine was measured using a2 hr. incubation at 4° C. Incubations contained about 500 ug of proteinand were conducted in 12 mm×75 mm polypropylene test tubes in a finalincubation volume of 250 ul. The incubation buffer was Krebs-RingersHEPES containing 200 mM TRIS buffer, pH 7.5. The binding reaction wasterminated by filtration of the protein containing bound ligand ontoglass fiber filters (Micro Filtration Systems) that had been soaked inbuffer containing 0.5 percent polyethyleneimine. Filtration vacuum was-50 to -100 torr. Each filter was washed five times with 3 ml ofice-cold buffer. The filtration apparatus was cooled to 2° C. before useand was kept cold through the filtration process. Nonspecific bindingwas determined by inclusion of 10 uM nonradioactive nicotine in theincubations.

The inhibition of L- ³ H!nicotine binding by test compounds wvasdetermined by including one of eight different concentrations of thetest compound in the incubation. Inhibition profiles were measured using10 nM L- ³ H!nicotine and IC₅₀ values were estimated as theconcentration of compound that inhibited 50 percent of specific L- ³H!nicotine binding. Inhibition constants (Ki values), reported in nM,were calculated from the IC₅₀ values using the method of Cheng et al.,Biochem. Pharmacol., Vol. 22, pp. 3099-3108 (1973).

Determination of Dopamine Release

Dopamine release was measured by preparing synaptosomes from thestriatal area of rat brain obtained from Sprague-Dawley rats generallyaccording to the procedures set forth by Nagy et al., J. Neurochem.,Vol. 43, pp. 1114-1123 (1984). Striata from 4 rats were homogenized in 2ml of 0.32M sucrose buffered with 5 mM HEPES (pH 7.5), using aglass-Teflon tissue grinder. The homogenate was diluted to 5 ml withadditional homogenization solution and centrifuged at 1,000×g for 10min. This procedure was repeated on the new pellet and the resultingsupernatant was centrifuged at 12,000×g for 20 min. A 3 layerdiscontinuous Percoll gradient consisting of 16 percent, 10 percent and7.5 percent Percoll in HEPES-buffered sucrose was made with the finalpellet dispersed in the top layer. After centrifugation at 15,000×g for20 min., the synaptosomes were recovered above the 16 percent layer witha Pasteur pipette, diluted with 8 ml of perfusion buffer (128 mM NaCl,2.4 mM KCl, 3.2 mM CaCl₂, 1.2 mM KH₂ PO₄, 1.2 mM MgSO₄, 25 mM HEPES pH7.4, 10 mM dextrose, 1 mM ascorbate, 0.01 mM pargyline), and centrifugedat 15,000×g for 20 min. The new pellet was collected and re-suspended inperfusion buffer. The synaptosome suspension was incubated for 10 min.at 37° C. ³ H!-Dopamine (Amersham, 40-60 Ci/mmol) was added to thesuspension to give a final concentration of 0.1 uM, and the suspensionwas incubated for another 5 min. Using this method, 30 to 90 percent ofthe dopamine was taken up into the synaptosomes, as determined byscintillation counting following filtration through glass fiber filterssoaked with 0.5 percent polyethyleneimine. A continuous perfusion systemwas used to monitor release following exposure to each ligand.Synaptosomes were loaded onto glass fiber filters (Gelman type A/E).Perfusion buffer was dripped onto the filters (0.2-0.3 ml/min.) andpulled through the filters with a peristaltic pump. Synaptosomes werewashed with perfusion buffer for a minimum of 20 min. before addition ofthe ligand. After the addition of 0.2 ml of a solution containingvarious concentrations of ligand, the perfusate was collected intoscintillation vials at 1 min. intervals and the dopamine released wasquantified by scintillation counting. Peaks of radioactivity releasedabove background were summed and the average basal release during thattime was subtracted from the total. Release was expressed as apercentage of release obtained with an equal concentration of(S)-(-)-nicotine.

Determination of Log P

Log P values (log octanol/water partition coefficient), which have beenused to assess the relative abilities of compounds to pass across theblood-brain barrier (Hansch, et al., J. Med. Chem., Vol. 11, p. 1(1968)), were calculated according to the methods described byHopfinger, Conformational Properties of Macromolecules, Academic Press(1973) using Cerius² software package by Molecular Simulations, Inc. forSample Nos. 1-3, 5-8 and C-1, and Bodor, University of Florida (1991)using the BLogP software package by CAChe Scientific, Inc. for SampleNo. 4.

Determination of Interaction with Muscle

Human muscle activation was established on the human clonal lineTE671/RD which is derived from an embryonal rhabdomyosarcoma (Strattonet al., Carcinogen, Vol. 10, pp. 899-905 (1989)). As evidenced throughpharmacological (Lukas, J. Pharmacol. Exp. Ther., Vol. 251, pp. 175-182(1989)), electrophysiological (Oswald et al, Neurosci. Lett., Vol. 96,pp. 207-212 (1989)), and molecular biological studies (Luther et al., J.Neurosci., Vol. 9, pp. 1082-1096 (1989)) these cells express muscle-likenicotinic receptors. Nicotinic acetylcholine receptor (nAChR) functionwas assayed using ⁸⁶ Rb⁺ efflux according to a method described by Lukaset al., Anal. Biochem., Vol. 175, pp. 212-218 (1988). Dose-responsecurves were plotted and the concentration resulting in half maximalactivation of specific ion flux through nicotinic receptors determinedfor human muscle and rat ganglionic preparations (EC50). The maximalactivation for individual compounds (Emax) was determined as apercentage of the maximal activation induced by (S)-(-)-nicotine.

Determination of Interaction with Ganglia

Ganglionic effects were established on the rat pheochromocytoma clonalline PC12, which is a continuous clonal cell line of neural crest originderived from a tumor of the rat adrenal medulla expressingganglionic-type neuronal nicotinic receptors (see Whiting et al.,Nature, Vol. 327, pp. 515-518 (1987); Lukas, J. Pharmacol. Exp. Ther.,Vol. 251, pp. 175-182 (1989); Whiting et al., Mol. Brain Res. , Vol. 10,pp. 61-70 (1990)). Discussion concerning the heterogeneity of nicotinicreceptors subtypes is set forth in Lukas et al., Internatl. ReviewNeurobiol., Vol. 34, pp. 25-130 (1992). Acetylcholine nicotinicreceptors expressed in rat ganglia share a verv high degree of homologywith their human counterparts. See. Fornasari et al., Neurosci. Lett.,Vol. 111, pp. 351-356 (1990) and Chini et al., Proc. Natl. Acad. Sci.USA, Vol. 89, pp. 1572-1576 (1992). Both clonal cell lines describedabove were maintained in proliferative growth phase according to routineprotocols (Bencherif et al., Mol. Cell. Neurosci., Vol. 2, pp. 52-65,(1991) and Bencherif et al., J. Pharmacol. Exp. Ther., Vol. 257, pp.946-953 (1991)). Intact cells on dishes were used for functionalstudies. Routinely, sample aliquots were reserved for determination ofprotein concentration using the method of Bradford, Anal. Biochem., Vol.72, pp. 248-254 (1976) with bovine serum albumin as the standard.

Nicotinic acetylcholine receptor (nAChR) function was assayed using ⁸⁶Rb⁺ efflux according to a method described by Lukas et al., Anal.Biochem., Vol. 175, pp. 212-218 (1988). Cells were plated in 35-mmdiameter wells of 6-well dishes for at least 48 hours and loaded for atleast 4 hours at 37° C. in a medium containing serum, and 1 μCi/ml ⁸⁶Rb⁺. Following removal of the loading medium, cells were quickly washedthree times with label-free Ringer's solution and exposed for 4 minutesat 20° C. to 900 μl of Ringer's containing the indicated concentrationof compound to be tested (to define total efflux) or in addition to 100μM mecamylamine (to define non-specific efflux). The medium was removedand ⁸⁶ Rb⁺ was quantitated using Cerenkov detection (see Lukas et al.,Anal. Biochem., Vol. 175, pp. 212-218 (1988)). Specific ion efflux wasdetermined as the difference in isotope efflux between total andnon-specific efflux samples. Dose-response curves were plotted and theconcentration resulting in half maximal activation of specific ion fluxthrough nicotinic receptors determined for human muscle and ratganglionic preparations (EC50). The maximal activation for individualcompounds (Emax) was determined as a percentage of the maximalactivation induced by (S)-(-)-nicotine.

Data are presented in Table I.

                  TABLE I    ______________________________________               Dopamine Release                           Muscle   Ganglion    Sample          Ki             EC50  Emax    Effect (%                                              Effect (%    No.   (nM)   logP    (nM)  (% nicotine)                                       nicotine)                                              nicotine)    ______________________________________    C-1*   2     0.71     115  100     100    100    1     269    -0.30   4360  113     0      0    2     86     0.04    5800  77      4      1    3     22     1.13    4000  95      0      0    4     58     1.82    8350  87      7      59    5     77     1.39    11339 88      0      0    6     176    1.92     219  60      2      4    7     910    1.51    ND    72      0      31    8     16     1.39    1470  80      15     0    ______________________________________     *not an example of the invention     ND = not determined

The data in Table I indicate that the compounds have the capability ofpassing the rain barrier by virtue of their favorable logP values,binding to high affinity CNS nicotinic receptors as indicated by theirlow binding constants, and activating CNS nicotinc recptors of a subjectand causing neurotransmitter release, thereby demonstrating knownnicotnic pharmacology. Thus, the data indicate that such compounds havethe capability of being useful in treating CNS disorders involvingnicotinic cholinergic systems. Furthermore, the data indicate that thecompounds do not cause any appreciable effects at muscle sites andganglionic sites, thus indicating a lack of undesirable side effects insubjects receiving administration of those compounds.

What is claimed is:
 1. A method for providing prevention or treatment ofattention deficit disorder in a subject in need thereof, the methodcomprisin administering to said subject an effective amount of acompound having the formula: ##STR3## where X is nitrogen or carbonbonded to a substituent species characterized as having a sigma m valuebetween about -0.3 and about 0.75; n is an integer which ranges from 1to 5; Z' and Z" individually represent hydrogen or alkyl containing oneto five carbon atoms; A, A' and A" individually represent hydrogen,alkyl containing one to seven carbon atoms, or halo; the dashed line inthe structure represents a C--C single bond, a C--C double bond or aC--C triple bond; the wavy line in the structure represents a cis (Z) ortrans (E) form of a compound when the dashed line is a C--C double bond;and X' represent CH₂ when the dashed line is a C--C single bond, CH whenthe dashed line is a C--C double bond, and C when the dashed line is aC--C triple bond.
 2. The method of claim 1, whereby the compound isselected from the group consisting of (E)-metanicotine,(Z)-metanicotine, N-methyl-4-(3pyrindyl)-3-butyne-1-amine,(E)-N-methyl-4-(3-(6-methylpyrindin)yl)-3-butene-1-amine,(E)-4-(5-pyrimidinyl)-3-butene-1-amine,(E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine,(E)-4-(3-(5-methoxypyridin)yl)-3 -butene-1-amine or(E)-N-methyl-4-(3-(5-methoxypyridin)yl)-3-butene-1-amine.
 3. The methodof claim 2 whereby the effective amount of compound administered isamount of at least about 1 mg/24 hr./subject and does not exceed about500 mg/24 hr./subject.
 4. The method of claim 2 whereby the effectiveamount of compound administered is amount of at least about 10 mg/24hr./subject and does not exceed about 400 mg/24 hr./subject.
 5. Themethod of claim 2 whereby the effective amount of compound administeredis such that the subject does not experience a concentration of compoundin plasma which does not exceed 500 ng/ml.
 6. The method of claim 1whereby X is nitrogen or carbon bonded to a substituent speciescharacterized as having a sigma m n value less than 0; n is an integerwhich ranges from 1 to 3; Z' and Z" individually represent hydrogen,methyl or isopropyl; A and A' represent hydrogen; and A" representshydrogen, methyl or ethyl.
 7. The method of claim 1 whereby X isnitrogen or carbon bonded to a substituent species characterized ashaving a sigma m value less than 0; n is an integer which ranges from 1to 3; Z' and Z" individually represent hydrogen, methyl or isopropyl; Aand A' represent hydrogen; and A" represent hydrogen, methyl or ethyl.8. The method of claim 1 whereby n is an integer which ranges from 1 to3; Z' and Z" individually represent hydrogen, methyl or isopropyl; A andA' represent hydrogen; A" represents hydrogen, methyl or ethyl; and whenthe dashed line is a C--C double bond and the compound has the trans (E)form, the substituent species is characterized as having a sigma m valuenot equal to
 0. 9. The method of claim 1 whereby Z is nitrogen or carbonbonded to a substituent species characterized as having a sigma m valuebetween about -0.25 and about 0.6; n is an integer which ranges from 1to 3; Z' and Z" individually represent hydrogen, methyl or isopropyl; Aand A' represent hydrogen; and A" represents hydrogen, methyl or ethyl.10. The method of claim 1 whereby X is nitrogen; n is an integer whichranges from 1 to 3; Z' and Z" individually represent hydrogen, methyl orisopropyl; A and A' represent hydrogen; and A' represents hydrogen,methyl or ethyl.
 11. A method for providing prevention or treatment ofattention deficit disorder in a subject in need thereof, the methodcomprising administering to a subject an effective amount of a compoundhaving the formula: ##STR4## where X is nitrogen or carbon bonded to asubstituent species characterized as having a sigma m value betweenabout -0.3 and about 0.75; n is an integer which ranges from 1 to 5; Z'and Z" individually represent hydrogen or alkyl containing one to fivecarbon atoms; A, A' and A" individually represent hydrogen, alkylcontaining one to seven atoms, or halo; the dashed line in the stucturerepresents a C--C double bond; the wavy line in the structure representsa cis (Z) or trans (E) form of the compound; and X' represents CH. 12.The method of claim 11 whereby the compound is selected from the groupconsisting of (E)-metanicotine, (Z)-metanicotine,N-methyl-4-(3pyrindyl)-3-butyne-1-amine,(E)-N-methyl-4-(3-(6-methylpyrindin)yl)-3-butene-1-amine,(E)-4-(5-pyrimidinyl)-3-butene-1-amine,(E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine,(E)-4-(3-(5-methoxypyridin)yl)-3-butene-1-amine or(E)-N-methyl-4-(3-(5-methoxypyridin)yl)-3-butene-1-amine.
 13. The methodof claim 12 whereby the effective amount of compound administered isamount of at least about 1 mg/24 hr./subject and does not exceed about500mg/24 hr./subject.
 14. The method of claim 12 whereby the effectiveamount of compound administered is amount of at least about 10 mg/24hr./subject and does not exceed about 400 mg/24 hr./subject.
 15. Themethod of claim 12 whereby the effective amount of compound administeredis such that the subject does not experience a concentration of compoundin plasma which does not exceed 500 ng/ml.
 16. The method of claim 11whereby X is nitrogen or carbon bonded to a substituent speciescharacterized as having a sigma m value less than 0; n is an integerwhich ranges from 1 to 3; Z' and Z" individually represent hydrogen,methyl or isopropyl; A and A' represent hydrogen; and A" representshydrogen, methyl or ethyl.
 17. The method of claim 11 whereby Z isnitrogen or carbon bonded to a substituent species characterized ashaving a sigma m value between about -0.25 and about 0.6; n is aninteger which ranges from 1 to 3; Z' and Z" individually representhydrogen, methyl or isopropl; A and A' represent hydrogen; A" representshydrogen, methyl or ethyl.
 18. The method of claim 11 whereby X isnitrogen; n is an integer which ranges from 1 to 3; Z' and Z"individually represent hydrogen, methyl or isopropyl; A and A' representhydrogen; and A" represents hydrogen, methyl or ethyl.